The objectives of this proposal are to characterize new serologically detectable alloantigens of the human major histocompatibility system (MHS), to evaluate these alloantigens as markers for specific disease susceptibility and/or postulated immune response (IR) genes. Extensive animal studies have shown the existence of specific IR genes and disease susceptibility genes linked to the species major histocompatibility loci. Studies in man are consistent with the animal models, particularly with respect to associations between specific diseases and human MHS (HLA) antigens. Because further characterization of HLA antigens, especially the new B cell alloantigens, may provide better genetic markers for human IR or disease susceptibility genes, a major effort will be directed to testing a rich source of human alloantisera, i.e., parous female blood donors, for antibodies identifying new HLA antigens. Sera will be screened against peripheral blood lymphocytes and B lymphocytes from large panels of unrelated donors and also from well-studied families to show both associations and linkage. Lysostrip and/or antibody or F(ab')2 blocking will be used to confirm nonidentity with previously defined antibodies. Xenogeneic antibodies, consisting of murine monoclonal anti-(human) lymphocyte antibodies, derived by collaborators from hybridoma cultures will also be tested against the same cell panels for suitability as a source of MHS typing reagents. The mechanism of antibody mediated cytotoxicity will also be investigated by studying a system in which antibodies bind to a crossreactive antigen but fail to lyse cells possessing that antigen (i.e., the CYNAP phenomena). Finally, a new method for detecting platelet surface antigens and drug antigens which adsorb to platelet surfaces has also been developed and is under clinical study.